Increase in serotonin (5-HT) transmission has profound antidepressant effects and has been associated with an increase in adult neurogenesis. The present study was aimed at screening the 5-HT receptor subtypes involved in the regulation of cell proliferation in the subgranular layer (SGL) of the dentate gyrus (DG) and the subventricular zone (SVZ) and to determine the long-term changes in adult neurogenesis. The 5-HT1A, 5-HT1B, and 5-HT2 receptor subtypes were chosen for their implication in depression and their location in/ or next to these regions. Using systemic administration of various agonists and antagonists, we show that the activation of 5-HT1A heteroreceptors produces similar increases in the number of bromodeoxyuridine-labeled cells in the SGL and the SVZ (about 50% over control), whereas 5-HT2A and 5-HT2C receptor subtypes are selectively involved in the regulation of cell proliferation in each of these regions. The activation of 5-HT2C receptors, largely expressed by the choroid plexus, produces a 56% increase in the SVZ, while blockade of 5-HT2A receptors produces a 63% decrease in the number of proliferating cells in the SGL. In addition to the influence of 5-HT1B autoreceptors on 5-HT terminals in the hippocampus and ventricles, 5-HT1B heteroreceptors also regulate cell proliferation in the SGL. These data indicate that multiple receptor subtypes mediate the potent, partly selective of each neurogenic zone, stimulatory action of 5-HT on adult brain cell proliferation. Furthermore, both acute and chronic administration of selective 5-HT1A and 5-HT2C receptor agonists produce consistent increases in the number of newly formed neurons in the DG and/or olfactory bulb, underscoring the beneficial effects of 5-HT on adult neurogenesis.

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Characterizing the mechanisms by which endogenous factors stimulate neurogenesis is of special interest in view of the possible implication of newly generated cells in hippocampal functions or disorders. The aim of this study was to determine whether serotonin (5-HT) and oestradiol (E2) act through a common pathway to increase cell proliferation in the adult dentate gyrus (DG). We also investigated the effects of long-lasting changes in oestrogen levels on cell proliferation. Combining ovariectomy with inhibition of 5-HT synthesis using p-chlorophenylalanine (PCPA) treatment produced approximately the same decreases in the number of bromodeoxyuridine (BrdU) and PSA-NCAM immunolabelled cells in the subgranular layer as ovariectomy alone. Administration of 5-hydroxytryptophan (5-HTP) restored cell proliferation primarily decreased by ovariectomy, whereas oestradiol was unable to reverse this change in ovariectomized rats treated with PCPA. These findings demonstrate that 5-HT mediates oestrogen stimulation of cell proliferation in adult dentate gyrus. However, increase in ovarian hormones during pregnancy has no effect on dentate cell proliferation. This finding suggests that concomitant changes in other factors, such as glucocorticoids, may counterbalance the positive regulation of cell proliferation by 5-HT and oestradiol. Finally, oestrogen may regulate structural plasticity by stimulating PSA-NCAM expression independently of neurogenesis, as shown for instance by the increases in the number of PSA-NCAM labelled cells in pregnants. As 5-HT and oestrogen are involved in mood disorders, our data suggest that the positive regulation of cell proliferation and neuroplasticity by these two factors may contribute to restore hippocampal connectivity in depressive patients.

A superfusion system was used in order to investigate the ionic requirements of luteinizing hormone releasing hormone (LHRH) and somatostatin (SRIF) release from mediobasal hypothalamic (MBH) slices of male adult rats. Slices were superfused with Hepes-buffered Locke medium at 37 °C in an atmosphere of Ch 95%–CO2 5% for 1 h. Bacitracin (2 × 10^–5M) was added to the medium to prevent enzymatic degradation of neuropeptides. Depolarizing agents such as potassium (K⁺) or veratridine stimulated LHRH and SRIF release in a dose-dependent manner. Maximal effect was obtained with K⁺ 56 mM and veratridine 50 µM. The depolarizing effect of K⁺ 56 mM was specific and not due to the hypertonicity of the medium used. Neither Mg²⁺ nor chlorine was needed for the spontaneous or K⁺-evoked release of LHRH and SRIF. The amplitude of the secretory response to K⁺ 56 mM was related to Ca²⁺ concentration tested in the range of 0.2–8.8 mM; maximal responses were obtained between 0.8 and 1.8 mM. Removal of Ca²⁺ from the medium with or without replacement by Mg²⁺, as well as administration of voltage-sensitive Ca²⁺ channel blockers (D-600 10^–4M, Mn²⁺ 3 mM) blocked both K⁺ and veratridine induced neuropeptide release. When sodium channels and the ‘early’ calcium channels were blocked by tetrodotoxin (5 × 10^–7M) the stimulatory effect of veratridine was completely blocked whereas the stimulation of K⁺ was unaffected. These experiments indicate that: (1) both K⁺ and veratridine induced-LHRH and SRIF release is a Ca2⁺-dependent process; (2) Ca²⁺ concentration is critical for the amplitude of the secretory response; (3) the main Ca²⁺ channel involved in neuropeptide release corresponds to the voltage-sensitive Ca²⁺ channel, and (4) neither magnesium or chlorine is needed for either spontaneous or evoked release of LHRH and SRIF.